Mechanistic Insights into the Propagation Cycle of the Hofmann–Löffler–Freytag Reaction: Halogen vs Hydrogen Atom Transfer

Zubčić, Gabrijel; Andrijanić, Luka; Džeba, Iva; You, Jiangyang; Friganović, Tomislav; Portada, Tomislav; Pavić, Kristina; Bešić, Erim; Vrček, Valerije; Šakić, Davor (2025) Mechanistic Insights into the Propagation Cycle of the Hofmann–Löffler–Freytag Reaction: Halogen vs Hydrogen Atom Transfer. The Journal of Organic Chemistry, 90 (14). pp. 4873-4887. ISSN 0022-3263

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Abstract

The Hofmann−Löffler−Freytag (HLF) reaction is a method that employs N-chlorinated precursors in radical-mediated rearrangement cycles to synthesize pyrrolidine rings and C−H functionalized products. This study aims to elucidate the mechanism of the propagation cycle, identify the rate-limiting step, and uncover the factors influencing the regioselectivity of the HLF reaction. Combining experimental techniques-laser flash photolysis (LFP), electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR)-with computational density functional theory (DFT) calculations and kinetic modeling, we challenge the previous assumption that the hydrogen atom transfer (HAT) step was rate-limiting and regioselectivity was under both thermodynamic and kinetic control. We have identified that the halogen atom transfer (XAT) step in the propagation cycle of the HLF reaction follows pseudo-first-order kinetics and has the largest transition-state barrier. Additionally, we observed that regioselectivity is exclusively controlled by the intramolecular hydrogen atom transfer kinetics, while no thermodynamic preference exists in the formation of C6- and C5-chlorinated products. Our work predicts how to accelerate the HLF reaction and how we can control the regioselectivity by the smarter selection of substrates based on calculations, which could provide better control of the reaction when implemented in organic synthesis.

Item Type:	Article
Uncontrolled Keywords:	Propagation cycle; LFP; EPR; NMR; DFT calculations; kinetic modelling; rate-limiting step; regioselectivity; radical-mediated rearrangement; mechanistic study; hydrogen atom transfer (HAT); halogen atom transfer (XAT)
Subjects:	NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Theoretical Chemistry NATURAL SCIENCES > Chemistry > Organic Chemistry
Divisions:	Division of Materials Chemistry Division of Organic Chemistry and Biochemistry Division of Physical Chemistry
Projects:	Project title Project leader Project code Project type Svjetlošću pogonjena funkcionalizacija nereaktivnih pozicija korištenjem oksidacijske aminacije-LIGHT-N-RING Davor Šakić; Mirsada Ćehić UIP-2020-02-4857 HRZZ Kriogeni centar Instituta za fiziku-KaCIF Nikolina Novosel; Josip Buhin KK.01.1.1.02.0012 EK Jačanje znanstveno-istraživačkih i inovacijskih kapaciteta Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu-FarmInova Jasmina Lovrić KK.01.1.1.02.0021 EK In-silico potpomognut dizajn supstrata za hvatanje CO2 u katalitičkoj formaciji karbonata i karbamata-INDICATIOR Dean Marković; Karlo Wittine; Maja Abram; Laclef Sylvain; Petra Grbčić; Gabriela Ambrožić; Dario Matulja; Mirela Sedić; Valerije Vrček IP-2019-04-8846 HRZZ Kemijska sudbina zabrinjavajućih farmaceutika u okolišu: eksperimentalno i računalno istraživanje produkata razgradnje i njihovih ekotoksikoloških svojstava Valerije Vrček IP-2022-10-2634 HRZZ Hrvatski znanstveni i obrazovni oblak Ivan Marić KK.01.1.1.08.0001 UNSPECIFIED
Depositing User:	Iva Džeba
Date Deposited:	24 Apr 2025 07:19
URI:	http://fulir.irb.hr/id/eprint/9725
DOI:	10.1021/acs.joc.4c02997

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